Previous studies of the obese-hyperglycemic syndrome in C57BL/6J ob/ob mice have shown that there is a developmental sequence in the behavioral, growth, and metabolic-endocrine abnormalities. As early as 7 days of age hypometabolism, hyperinsulinemia, obesity, hyperphagia, and hypoglycemia are well established. Shortly later, during the normal weaning period (17 to 28 days of age), disturbances of glycoregulation, i.e. fasting hyperglycemia, glucose intolerance, and in vivo insulin insensitivity, rapidly appear. These disturbances become progressively more severe during the next several months. In the coming year we will 1) continue investigation of the factors responsible for the development of diabetes in the periweaning period. Of top priority in these investigations will be the determination of the insulin sensitivity (glucose transport and metabolism) of a soleus muscle preparation at each stage of the developing syndrome. In addition, we will describe the times of origin of the hyperglucagonemia and hypercorticoidism that characterize the fully developed syndrome, 2) test the feasibility of using differences in cell surface proteins as a genotype marker in order the expand our studies to fetal mice, and finally 3) continue our studies of the in vivo dynamics of corticosterone and cortisol production in these animals which display hypercorticoidism throughout much of their adult life. These final studies will include test of suppressive agents (o,p'-DDD, metapyrone) on the reproductive physiology and metabolic disturbances of ob/ob mice, use of exogenous ACTH to reproduce the ob/ob syndrome in lean C57BL/6J mice, and examine further the hypothesis that the chronic administration of porcine ACTH will cause a shift in adrenal corticoid synthesis to increased cortisol production.